Abstract | CONTEXT:
Somatostatin (SST) and dopamine (DA) inhibit growth hormone (GH) secretion and proliferation of GH-secreting pituitary adenomas (GHomas) through binding to SSTR2 and D2R receptors. Chimeric SST-DA compounds (Dopastatins) display increased potency in inhibiting GH secretion, as compared with individual SST or DA analogs (alone or combined). OBJECTIVE: To assess the efficacy of a second-generation dopastatin, TBR-065, in suppressing GH secretion from human GH- and GH/ prolactin(PRL)-omas. DESIGN: We compared the ability of TBR-065 to inhibit GH secretion from primary cultures of human GH- or GH/PRLoma cells to that of the first generation dopastatin, TBR-760 (formerly BIM-23A760), octreotide (OCT) and cabergoline (CAB), the later either alone or combined. We investigated whether there was any impact of BIM-133, the metabolite of TBR-065, on the ability of TBR-065 to inhibit GH in these cultures. METHODS: 17 GH- and GH/PRLomas were included in this study. Inhibition of GH secretion by TBR-065, TBR-760, OCT and CAB (0.1 pM to 0.1 µM) was assessed over a period of 8 h. RESULTS: All tumors expressed SSTR2 and D2R mRNAs. GH suppression was higher with TBR-065 as compared with TBR-760 (Emax = 57 ± 5.6% vs. 41.1 ± 12.5%, respectively, p < 0.001) or with OCT + CAB (Emax = 56.8 ± 7.2% vs. 44.4 ± 9.4%, p < 0.001). BIM-133 did not have any impact on the activity of TBR-065. CONCLUSION: TBR-065 has significantly improved efficacy in suppressing GH secretion as compared to current available therapies and may represent a new promising option for the treatment of acromegaly.
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Authors | Thomas Cuny, Thomas Graillon, Célines Defilles, Rakesh Datta, Shengwen Zhang, Dominique Figarella-Branger, Henry Dufour, Grégory Mougel, Thierry Brue, Tanya Landsman, Heather A Halem, Michael D Culler, Anne Barlier, Alexandru Saveanu |
Journal | Pituitary
(Pituitary)
Vol. 24
Issue 3
Pg. 351-358
(Jun 2021)
ISSN: 1573-7403 [Electronic] United States |
PMID | 33433890
(Publication Type: Journal Article)
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Chemical References |
- Receptors, Dopamine D2
- Receptors, Somatostatin
- Human Growth Hormone
- Somatostatin
- Cabergoline
- Octreotide
- Dopamine
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Topics |
- Adenoma
(drug therapy)
- Cabergoline
- Dopamine
- Human Growth Hormone
- Humans
- Octreotide
(pharmacology)
- Pituitary Neoplasms
(drug therapy)
- Receptors, Dopamine D2
- Receptors, Somatostatin
(genetics)
- Somatostatin
(pharmacology)
- Tumor Cells, Cultured
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